US3914253A - 5-Oxo-6-substituted-cyclopent-{8 f{9 -indole-2-carboxylic acids - Google Patents
5-Oxo-6-substituted-cyclopent-{8 f{9 -indole-2-carboxylic acids Download PDFInfo
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- US3914253A US3914253A US448151A US44815174A US3914253A US 3914253 A US3914253 A US 3914253A US 448151 A US448151 A US 448151A US 44815174 A US44815174 A US 44815174A US 3914253 A US3914253 A US 3914253A
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- indole
- oxo
- substituted
- cyclopent
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- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- -1 5-Oxo-6-substituted-cyclopent-(f)-indole-2-carboxylic acids Chemical class 0.000 abstract description 14
- 238000000034 method Methods 0.000 abstract description 8
- 150000001408 amides Chemical class 0.000 abstract description 7
- 150000002148 esters Chemical class 0.000 abstract description 7
- 150000003839 salts Chemical class 0.000 abstract description 7
- 239000000203 mixture Substances 0.000 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical class C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000002934 diuretic Substances 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 159000000001 potassium salts Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000005431 alkyl carboxamide group Chemical group 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000000894 saliuretic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011591 potassium Chemical group 0.000 description 1
- 229910052700 potassium Chemical group 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered
Definitions
- ester and amide derivatives thereof; wherein R is lower pounds of the present invention are effective diuretic and saluretic agents which can be used in the treatment of conditions associated with electrolyte and fluid retention such as edema and hypertension.
- the compounds of this invention when administered in therapeutic dosages in conventional vehicles, effectively reduce the amount of sodium and chloride ions in the body, lower dangerous excesses of fluid levels to acceptable levels and in general alleviate the conditions associated with edema and hypertension.
- substituted indoles (II, above) are prepared according to the procedure of US. Pat. No.
- ester, salt and amide derivatives of the compounds of this invention which are prepared by conventional methods well known to those skilled in the art.
- the ester derivative may be prepared by reaction of the compounds of this invention with an alcohol, for example, a lower alkanol.
- the amide derivatives may be prepared by converting the 2-carboxylic acids of the present invention to their corresponding acid chloride by treatment'with thionyl chloride followed by treating said acid chloride with ammonia, an
- ester and amide (and salt) derivatives of the instant invention will be apparent to one having ordinary skill in the art and to the extent that said derivatives are both nontoxic and pharmaceutically accpetable, they are functionally equivalent as diuretics and saluretics when compared to the carboxylic acid form.
- EXAMPLE 1 4-Chloro-5-oxo-6-ethylcyclopent[f] indole-2- carboxylic acid
- EXAMPLE 2 l,4-Dimethyl-5-oxo-6-ethylcyclopent[f]indole-2- carboxylic acid
- a solution of l,4-dimethyl-5-(2-methylenebutyryl)- indle-2-carboxylic acid g.) in concentrated sulfuric acid (25 ml.) is stirred at 5560C. for 6 hours then poured into ice water (200' ml.) affording l,4-dimethyl- 5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid after filtering and drying.
- EXAMPLE 3 4-Methyl-5-oxo-6-ethylcyclopent[f] indole-2- carboxylic acid wherein R is methyl, cyclopentyl, and isopropyl; X is fluoro, bromo, ethyl and isopropyl; and R is methyl, and ethyl, there is obtained an equivalent amount of the corresponding indole of the present invention having the structure:
- novel compounds of this invention are diuretic and saluretic agents which can be administered in a wide variety of therapeutic dosages in conventional vehicles as, for example, by oral administration in the form of tablets or by intravenous injection.
- the daily dosage of the products may be varied over a wide range as, for example, in the form of scored tabletscontaining 5, 10, 25, 50, 100, 150, 250 and 500 mg. of the active ingredient.
- a suitable unit dosage form of the products of this invention can be administered by mixing 50 mg. of a 5- oxo-6-substituted-cyclopent[f]indole-2-carboxylic acid (I) or a suitable salt, ester or amide derivative thereof with a 149 mg. of lactose and 1 mg. of magnesium stea-fl rate and placing the 200 mg. mixture into a No. l gela sary to mix more than 200 mg. of ingredients together larger capsules may be employed.
- Compressed tablets 50 mg. of a 5- oxo-6-substituted-cyclopent[f]indole-2-carboxylic acid (I) or a suitable salt, ester or amide derivative thereof with a 149 mg. of lactose and 1 mg. of magnesium stea-fl rate and placing the 200 mg. mixture into a No. l gela sary to mix more than 200 mg. of ingredients together larger capsules may be employed.
- Compressed tablets 50 mg
- pills and other desired unit dosages can be prepared to incorporate the compounds of this invention by convention methods, and if desired, can be made up as elixirs or as injectable solutions by methods well known to pharmacists.
- An'effective amount of the drug is ordinarily supplied at a dosage level of from about 1 mg. to about 50 mg. per kilogram of body weight. Preferably the range is from about 1 mg. to 7 mg. per kg. of body weight. It is also within the scope of this invention tocombine 2 or more of the compounds of this invention in a unit dosage form or to combine 1 or more of the compounds of this invention with other known diuretics and saluretics or with desired therapeutic and or nu- 'tritive agents in unit dosage form.
- EXAMPLE 6 Dry-filled capsules containing 50 mg. of active ingredient per capsule.
- R is methyl or ethyl
- R is hydrogen, methyl or ethyl
- X is methyl or chloro
- R is ethyl; R is hydrogen; X is chloro; which is 4-chloro-5-oxo-6-ethylcyclopent[f]indole-Z- carboxylic acid and the sodium and potassium salts thereof.
- R is ethyl; R is methyl; X is methyl; which is l,4-dimethyl-5-oxo-6-ethylcyclopent[f]indole-2- carboxylic acid and the sodium and potassium salts thereof.
- R is ethyl; R is hydrogen; X is methyl; which is 4-methyl-5-oxo-6-ethylcyclopent[f]indole-2- carboxylic acid and the sodium and potassium salts thereof.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
5-Oxo-6-substituted-cyclopent-(f)-indole-2-carboxylic acids, the salt, ester and amide derivatives thereof are disclosed having diuretic-saluretic pharmacological activity. Also disclosed are pharmaceutical compositions comprising such compounds and methods of treatment comprising administering such compounds and compositions.
Description
United States Patent Cragoe, Jr. et al.
[4 Oct. 21, 1975 l 5-OXO-6-SUBSTITUTED-CYCLOPENT-[F]- lNDOLE-Z-CARBOXYLIC ACIDS [75] Inventors: Edward J. Cragoe, Jr., Lansdale;
Otto W. Woltersdorf, Jr., Chalfont,
both of Pa.
[73] Assignee: Merck & Co., Inc., Rahway, NJ.
[22] Filed: Mar. 4, 1974 21 Appl. No.: 448,151
UNITED STATES PATENTS 3,682,961 8/1972 Zergenyi et 260826.13 R
Primary Examiner-Lewis Gotts Assistant ExaminerS. P. Williams Attorney, Agent, or Firm-Michael C. Sudol, Jr.; J. Jerome Behan; James A. Arno [57] ABSTRACT 5-Oxo-6-substituted-cyclopent-[f]-indole-2-carb0xylic acids, the salt, ester and amide derivatives thereof are disclosed having diuretic-saluretic pharmacological activity. Also disclosed are pharmaceutical compositions comprising such compounds and methods of treatment comprising administering such compounds and compositions.
5 Claims, N0 Drawings 5-OXO-6-SUBSTITUTED-CYCLOPENT-[F]- ,INDOLE-Z-CARBOXYLIC ACIDS BACKGROUND OF THE INVENTION This invention relates to a class of compounds generically referred to as 5-oxo-6-substituted-cyclopent-[f]- indole-2-carboxylic acids having the structure;
and the nontoxic pharmacologicall'y acceptable salt,
ester and amide derivatives thereof; wherein R is lower pounds of the present invention are effective diuretic and saluretic agents which can be used in the treatment of conditions associated with electrolyte and fluid retention such as edema and hypertension. Thus, when administered in therapeutic dosages in conventional vehicles, the compounds of this invention, effectively reduce the amount of sodium and chloride ions in the body, lower dangerous excesses of fluid levels to acceptable levels and in general alleviate the conditions associated with edema and hypertension.
Thus it is an object of the present invention to provide the indole derivatives of the above general description and to provide processes for preparation of such compounds. Further, it is an object of this invention to provide pharmaceutical compositions comprising such indole derivatives and to provide methods of treatment comprising administering such compounds and compositions.
DETAILED DESCRIPTION OF THE INVENTION fir coon Lewis l-ce Acid -a fully enabling disclosure relative to all species em-' braced by structure II for purposes of practicing this invention. For this reason U.S. Pat. No. -3,682,96l is in-' corporated herein by reference.
In general the substituted indoles (II, above) are prepared according to the procedure of US. Pat. No.
3,682,961 by reacting under Friedel-Crafts conditions.
an appropriately substituted indole-2-carboxylic acid with a carboxylic acid halide or anhydride thereof:
wherein R has previously been defined and Q is halogen. When the first-mentioned acid halide (or anhydride thereof) is employed, the corresponding indole (II) is obtained from the resulting 5-alkanoyl Friedel- Crafts product via the Mannich intermediate obtained on treating the S-alkanoyl species with paraformaldehyde and a secondary organic amine.
Also included within the scope of this invention are the ester, salt and amide derivatives of the compounds of this invention which are prepared by conventional methods well known to those skilled in the art. Thus for example, the ester derivative may be prepared by reaction of the compounds of this invention with an alcohol, for example, a lower alkanol. The amide derivatives may be prepared by converting the 2-carboxylic acids of the present invention to their corresponding acid chloride by treatment'with thionyl chloride followed by treating said acid chloride with ammonia, an
appropriate mono-lower alkylamine, di-lower alkyla= mine or a hetero amine such as piperidine, morpholine and the like, to produce the corresponding amide compound. These and other equivalent methods for the preparation of the ester and amide (and salt) derivatives of the instant invention will be apparent to one having ordinary skill in the art and to the extent that said derivatives are both nontoxic and pharmaceutically accpetable, they are functionally equivalent as diuretics and saluretics when compared to the carboxylic acid form.
The following examples specifically illustrate, but do not limit, the present invention.
COOH
EXAMPLE 1 4-Chloro-5-oxo-6-ethylcyclopent[f] indole-2- carboxylic acid EXAMPLE 2 l,4-Dimethyl-5-oxo-6-ethylcyclopent[f]indole-2- carboxylic acid A solution of l,4-dimethyl-5-(2-methylenebutyryl)- indle-2-carboxylic acid g.) in concentrated sulfuric acid (25 ml.) is stirred at 5560C. for 6 hours then poured into ice water (200' ml.) affording l,4-dimethyl- 5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid after filtering and drying.
EXAMPLE 3 4-Methyl-5-oxo-6-ethylcyclopent[f] indole-2- carboxylic acid wherein R is methyl, cyclopentyl, and isopropyl; X is fluoro, bromo, ethyl and isopropyl; and R is methyl, and ethyl, there is obtained an equivalent amount of the corresponding indole of the present invention having the structure:
. COOM R I wherein M is hydrogen, sodium and potassium; R is methyl, cyclopentyl, and isopropyl; R is methyl and ethyl, X is fluoro, bromo, ethyl, and isopropyl, respectively.
EXAMPLE 4 N-Ethyl [4-chloro-5-oxo-6-ethylcyclopent[f]indole-2- carboxamide] A solution of 4-chloro-5-oxo-6-ethylcyclopent[flindole-2-carboxylic acid (0.6 g.) and thionyl chloride (0.3 ml.) in benzene (10 ml.) is refluxed for 1 hour. The solvent is distilled at reduced pressure and the residue is treated with benzene (20 ml.) and ethylamine (0.5 ml.). After 1 hour the reaction mixture is poured into water and extracted with ether which is washed with dilute hydrochloric acid and aqueous sodium bicarbonate. The ether solution is dried over magnesium sulfate and evaporated at reduced pressure to afford N-ethyl [4-chloro-5-oxo'-6- ethylcyclopent[f]indole-2-carboxamide EXAMPLE 5 Ethyl [4-chloro-5-oxo-6-ethylcyclopent[f]indole-2'- carboxylate] To a solution of 4-chloro-5 -oxo-6- ethylcyclopent[f]indole-2-carboxylic acid (8.0 g.) in ethanol (50 ml.) is added boron trifluoride etherate 13 ml.). The reaction mixture is refluxed for 0.5 hours, treated with water and cooled to afford ethyl [4-chloro- 5-oxo-6-ethylcyclopent[f]indole-2-carboxylate] after filtration and drying. v
The novel compounds of this invention are diuretic and saluretic agents which can be administered in a wide variety of therapeutic dosages in conventional vehicles as, for example, by oral administration in the form of tablets or by intravenous injection. Also, the daily dosage of the products may be varied over a wide range as, for example, in the form of scored tabletscontaining 5, 10, 25, 50, 100, 150, 250 and 500 mg. of the active ingredient.
A suitable unit dosage form of the products of this invention can be administered by mixing 50 mg. of a 5- oxo-6-substituted-cyclopent[f]indole-2-carboxylic acid (I) or a suitable salt, ester or amide derivative thereof with a 149 mg. of lactose and 1 mg. of magnesium stea-fl rate and placing the 200 mg. mixture into a No. l gela sary to mix more than 200 mg. of ingredients together larger capsules may be employed. Compressed tablets,
pills and other desired unit dosages can be prepared to incorporate the compounds of this invention by convention methods, and if desired, can be made up as elixirs or as injectable solutions by methods well known to pharmacists. An'effective amount of the drug is ordinarily supplied at a dosage level of from about 1 mg. to about 50 mg. per kilogram of body weight. Preferably the range is from about 1 mg. to 7 mg. per kg. of body weight. It is also within the scope of this invention tocombine 2 or more of the compounds of this invention in a unit dosage form or to combine 1 or more of the compounds of this invention with other known diuretics and saluretics or with desired therapeutic and or nu- 'tritive agents in unit dosage form.
The following example is included to illustrate the preparation of the representative dosage form.
EXAMPLE 6 Dry-filled capsules containing 50 mg. of active ingredient per capsule.
Per capsule 5-Oxo-4-chloro-6-ethyl-cyclopent- [f] indole-Z-carboxylic acid 50 mg. Lactose 149 mg. Magnesium stearate 1 mg. Capsule (Size No. l 200 mg.
Similar dry-filled capsules can be prepared by replacing the active ingredient of the above example by any of the other novel compounds of this invention.
What is claimed is:
1. A compound having the structural formula:
COOH
COOH
wherein R is methyl or ethyl; R is hydrogen, methyl or ethyl; and X is methyl or chloro; and the nontoxic pharmaceutically acceptable salt, lower alkyl ester, carboxamide, mono-N-lower alkyl carboxamide, diN-lower alkyl carboxamide, piperidide and morpholide derivative thereof.
3. A compound having the structural formula:
wherein R is ethyl; R is hydrogen; X is chloro; which is 4-chloro-5-oxo-6-ethylcyclopent[f]indole-Z- carboxylic acid and the sodium and potassium salts thereof.
4. A compound having the structural formula:
wherein R is ethyl; R is methyl; X is methyl; which is l,4-dimethyl-5-oxo-6-ethylcyclopent[f]indole-2- carboxylic acid and the sodium and potassium salts thereof.
5. A compound having the structural formula:
wherein R is ethyl; R is hydrogen; X is methyl; which is 4-methyl-5-oxo-6-ethylcyclopent[f]indole-2- carboxylic acid and the sodium and potassium salts thereof.
Claims (5)
1. A COMPOUND HAVING THE STRUCTURAL FORMULA:
2. A compound having the structural formula:
3. A compound having the structural formula:
4. A compound having the structural formula:
5. A compound having the structural formula:
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US448151A US3914253A (en) | 1974-03-04 | 1974-03-04 | 5-Oxo-6-substituted-cyclopent-{8 f{9 -indole-2-carboxylic acids |
| ZA00750249A ZA75249B (en) | 1974-03-04 | 1975-01-14 | 5-oxo-6-substituted-cyclopent-(f)-indole-2-carboxylic acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US448151A US3914253A (en) | 1974-03-04 | 1974-03-04 | 5-Oxo-6-substituted-cyclopent-{8 f{9 -indole-2-carboxylic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3914253A true US3914253A (en) | 1975-10-21 |
Family
ID=23779201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US448151A Expired - Lifetime US3914253A (en) | 1974-03-04 | 1974-03-04 | 5-Oxo-6-substituted-cyclopent-{8 f{9 -indole-2-carboxylic acids |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US3914253A (en) |
| ZA (1) | ZA75249B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040198749A1 (en) * | 2002-02-19 | 2004-10-07 | Parion Sciences, Inc. | Methods of using sodium channel blockers |
| US20040198747A1 (en) * | 2002-02-19 | 2004-10-07 | Parion Sciences, Inc. | Sodium channel blockers |
| US6903105B2 (en) | 2003-02-19 | 2005-06-07 | Parion Sciences, Inc. | Sodium channel blockers |
| US7745442B2 (en) | 2003-08-20 | 2010-06-29 | Parion Sciences, Inc. | Methods of reducing risk of infection from pathogens |
| US8669262B2 (en) | 2011-06-27 | 2014-03-11 | Parion Sciences, Inc. | 3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide |
| US9586911B2 (en) | 2013-12-13 | 2017-03-07 | Parion Sciences, Inc. | Arylalkyl- and aryloxyalkyl-substituted epthelial sodium channel blocking compounds |
| US9593084B2 (en) | 2012-12-17 | 2017-03-14 | Parion Sciences, Inc. | Chloro-pyrazine carboxamide derivatives with epithelial sodium channel blocking activity |
| US9695134B2 (en) | 2012-12-17 | 2017-07-04 | Parion Sciences, Inc. | 3,5-diamino-6-chloro-N-(n-(4-phenylbutyl)carbamimidoyl)pyrazine-2-carboxamide compounds |
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| US3682961A (en) * | 1970-08-19 | 1972-08-08 | Ciba Geigy Corp | 4-chloro-5-(2-methylene-butryl)-indole carboxylic acid |
-
1974
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- 1975-01-14 ZA ZA00750249A patent/ZA75249B/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3682961A (en) * | 1970-08-19 | 1972-08-08 | Ciba Geigy Corp | 4-chloro-5-(2-methylene-butryl)-indole carboxylic acid |
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Also Published As
| Publication number | Publication date |
|---|---|
| ZA75249B (en) | 1976-01-28 |
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